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Mutation at Reverse Transcriptase Codon 214 is Antagonist to Thymidine Analogue Mutations Type 2 Profiles and Predicts Virological Response to Thymidine Analogue-contaning cART Regimens only if TAM Type 1 Profiles Are Concomitantly Detected
Alessandro Cozzi-Lepri*1, L Ruiz2, F Ceccherini-Silberstein3, A Mocroft1, A Phillips1, J Gatell4, B Ledergerber5, P Reiss6, B Clotet2, J Lundgren7, and EuroSIDA Study Group
1Royal Free and Univ Coll Med Sch, London, UK; 2Univ Autonoma de Barcelona, Spain; 3Univ of Tor Vergata, Rome, Italy; 4Univ of Barcelona, Spain; 5Univ Hosp, Zürich, Switzerland; 6Univ of Amsterdam, The Netherlands; and 7Copenhagen HIV Prgm, Hvidovre, Denmark
Background: Previous studies have shown that polymorphism
214F of RT region (vs expected aminoacid
L in HBX2 strain) is antagonist to thymidine analogue
mutation (TAM)-2 profiles but its prognostic role to predict virological response to thymidine
analogue-containing therapy needs further investigation.
Methods: Patients of EuroSIDA
who started a thymidine analogue-containing cART regimen (therapy) for the first time and had a
genotypic test 6 months before starting therapy. We investigated the prevalence
of 214F according to specific TAM and TAM profiles concomitantly detected. We
then studied the ability of the amino acid at codon
214 (F vs L) to predict the 6-month viral load change
using a linear regression model. We adjusted for pre-therapy viral load, days
between starting therapy and 6-month viral load, whether previously ART-naïve,
number of active drugs in therapy besides the thymidine
analogue (calculated using Rega IS), use of zidovudine or stavudine and we
tested for interaction with concomitant detection of TAM or TAM profiles (TAM1: 41L, 210W, 215Y or TAM2: 67N, 70R, 219E/Q).
Results: We studied 474 patients who started a thymidine analogue-containing cART
(45.1% were previously ART-naïve, 49.8% zidovudine,
and 50.2% stavudine). Polymorphism 214F was detected
in 81.0% of patients (85.1% in ART-naïve, p
= 0.04). The proportions of patients with a TAM according to whether 214F or
214L was concomitantly detected were:
41L (28% vs 28%, p = 0.94), 67N (22% vs 41%, p = 0.0003), 70R (17% vs 39%, p = 0.0001),
210W (21% vs 24% p
= 0.52), 215F (5% vs 22%, p = 0.0001), 215Y (33% vs 21%, p = 0.03), 219Q (7% vs
30%, p = 0.0001), 219E (4% vs 14%, p = 0.0004).
214F was also significantly associated with TAM profiles (p = 0.0001): TAM1 (24% vs 6%), TAM2 (6% vs 28%), and absence
of TAM (69% vs 66%). The overall median 6-month viral
load reduction was 2.15 log10 copies/mL (95%CI 1.93 to 3.39). The association between
214F/L and virological response varied according to
the presence of specific TAM. The adjusted mean 6-month viral load reductions
comparing patients with 214F to those with 214L, according to the detection of
specific TAM, were (41M:+0.01, 41L:–1.15, interaction p = 0.0001; 210L:+0.01, 210W:–1.26, p = 0.0003; 215T:–0.11, 215Y:–0.65, p = 0.0004; no TAM:–0.29, TAM1:–1.71, TAM2:+0.66, p = 0.05).
Conclusions: Polymorphism 214F is less likely to be
detected in viruses harboring TAM2 profiles than in
those with no TAM. Furthermore, 214F is associated with reduced virological response to thymidine
analogue-containing cART when mutations of TAM1
profiles are also detected.
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